Cephalosporin-metronidazole antibiotic composition

ABSTRACT

An antibiotic product for delivering at least cephalosporin or Metronidazole that is comprised of three dosage forms with different release profiles with each of cephalosporin and Metronidazole being present in at least one of the dosage forms.

[0001] This application is a continuation-in-part of application Ser.No. 09/791,983, filed Feb. 22, 2000, which claims the priority of U.S.Provisional Application Serial No. 60/184,545 filed on Feb. 24, 2000,the disclosure of which is hereby incorporated by reference in itsentirety.

[0002] This invention relates to antibiotic compositions and the usethereof. More particularly, this invention relates to a composition forthe delivery of two or more antibiotics, and the use thereof.

[0003] In many cases, it is desirable to employ two differentantibiotics in the treatment of a bacterial infection, in that suchantibiotics may have complementary mechanisms of action that facilitatetreatment of the bacterial infection.

[0004] The present invention is directed to a new and improvedcomposition that delivers two or more antibiotics, and the use thereof,with the two antibiotics being cephalosporin and Metronidazole.

[0005] In accordance with an aspect of the present invention, there isprovided an antibiotic product for delivering at least two differentantibiotics that is comprised of at least three dosage forms eachcomprised of at least one antibiotic and a pharmaceutically acceptablecarrier, with one of the dosage forms including at least one of the atleast two antibiotics and at least one dosage form including at least asecond antibiotic of the at least two antibiotics, wherein one of theantibiotics is cephalosporin and the other antibiotic is Metronidazole.

[0006] Thus, for example, each of the dosage forms may include two ormore antibiotics, or one or two of the dosage forms may include only oneof the two or more antibiotics and each of the remaining dosage formsmay include only one or more of the different antibiotics or two or moreof the antibiotics. Thus, in accordance with this aspect of theinvention, there is an antibiotic product for delivering at least twodifferent antibiotics wherein the product includes at least three dosageforms wherein each of the at least two antibiotics is present in atleast one of the three dosage forms. In each case, one of theantibiotics is cephalosporin and the other of the antibiotics isMetronidazole.

[0007] In a preferred embodiment each of the dosage forms has adifferent release profile, with one of the dosage forms being animmediate release dosage form.

[0008] In another aspect, the present invention is directed to treatinga bacterial infection by administering to a host in need thereof anantibiotic product as hereinabove and hereinafter described.

[0009] Thus, in accordance with an aspect of the present invention,there is provided a single or unitary antibiotic product that hascontained therein at least three antibiotic dosage forms, each of whichhas a different release profile, whereby the antibiotic contained ineach of the at least three dosage forms is released at different times,and wherein at least one of the dosage forms includes at leastcephalosporin and at least one of the dosage forms includes at leastMetronidazole. One or more of the dosage forms may include bothcephalosporin and Metronidazole.

[0010] In accordance with a further aspect of the invention, theantibiotic product may be comprised of at least four different dosageforms, each of which starts to release the antibiotic contained thereinat different times after administration of the antibiotic product.

[0011] The antibiotic product generally does not include more than fivedosage forms with different release times.

[0012] In accordance with a preferred embodiment, the antibiotic producthas an overall release profile such that when administered the maximumserum concentration of the total antibiotic released from the product isreached in less than twelve hours, preferably in less than eleven hours.In an embodiment, the maximum serum concentration of the totalantibiotic released from the antibiotic product is achieved no earlierthan four hours after administration.

[0013] In accordance with one preferred embodiment of the invention, oneof the at least three dosage forms is an immediate release dosage formwhereby initiation of release of antibiotic therefrom is notsubstantially delayed after administration of the antibiotic product.The second and third of the at least three dosage forms is a delayeddosage form (which may be a pH sensitive or a non-pH sensitive delayeddosage form, depending on the type of antibiotic product), wherebyantibiotic released therefrom is delayed until after initiation ofrelease of antibiotic from the immediate release dosage form. Moreparticularly, antibiotic release from the second of the at least twodosage forms achieves a C_(max) (maximum serum concentration in theserum) at a time after antibiotic released from the first of the atleast three dosage forms achieves a C_(max) in the serum, and antibioticreleased from the third dosage form achieves a C_(max) in the serumafter the C_(max) of antibiotic released from the second dosage form.

[0014] In one embodiment, the second of the at least two dosage formsinitiates release of antibiotic contained therein at least one hourafter the first dosage form, with the initiation of the releasetherefrom generally occurring no more than six hours after initiation ofrelease of antibiotic from the first dosage form of the at least threedosage forms.

[0015] In general, the immediate release dosage form produces a C_(max)for antibiotic released therefrom within from about 0.5 to about 2hours, with the second dosage form of the at least three dosage formsproducing a C_(max) for antibiotic released therefrom in no more thanabout four hours. In general, the C_(max) for such second dosage form isachieved no earlier than two hours after administration of theantibiotic product; however, it is possible within the scope of theinvention to achieve C_(max) in a shorter period of time.

[0016] As hereinabove indicated, the antibiotic product may contain atleast three or at least four or more different dosage forms. Forexample, the antibiotic released from the third dosage form reaches aC_(max) at a time later than the C_(max) is achieved for antibioticreleased from each of the first and second dosage forms. In a preferredembodiment, release of antibiotic from the third dosage form is startedafter initiation of release of antibiotic from both the first dosageform and the second dosage form. In one embodiment, C_(max) forantibiotic release from the third dosage form is achieved within eighthours.

[0017] In another embodiment, the antibiotic product contains at leastfour dosage forms, with each of the at least four dosage forms havingdifferent release profiles, whereby antibiotic released from each of theat least four different dosage forms achieves a C_(max) at a differenttime.

[0018] As hereinabove indicated, in a preferred embodiment, irrespectiveof whether the antibiotic contains at least three or at least fourdifferent dosage forms each with a different release profile, C_(max)for all the antibiotic released from the antibiotic product is achievedin less than twelve hours, and more generally is achieved in less thaneleven hours.

[0019] In a preferred embodiment, the antibiotic product is a once a dayproduct, whereby after administration of the antibiotic product, nofurther product is administered during the day; i.e., the preferredregimen is that the product is administered only once over a twenty-fourhour period. Thus, in accordance with the present invention, there is asingle administration of an antibiotic product with the antibiotic beingreleased in a manner such that overall antibiotic release is effectedwith different release profiles in a manner such that the overallC_(max) for the antibiotic product is reached in less than twelve hours.The term single administration means that the total antibioticadministered over a twenty-four hour period is administered at the sametime, which can be a single tablet or capsule or two or more thereof,provided that they are administered at essentially the same time.

[0020] Thus in accordance with an aspect of the invention, there isprovided a single dosage antibiotic product comprised of at least threeantibiotic dosage forms each having a different release profile witheach of the dosage forms including at least one of cephalosporin orMetronidazole and at least one of the three dosage forms including atleast cephalosporin and at least one of the dosage forms including atleast Metronidazole. Each of the dosage forms of antibiotic in apharmaceutically acceptable carrier may have one or more antibiotics.

[0021] It is to be understood that when it is disclosed herein that adosage form initiates release after another dosage form, suchterminology means that the dosage form is designed and is intended toproduce such later initiated release. It is known in the art, however,notwithstanding such design and intent, some “leakage” of antibiotic mayoccur. Such “leakage” is not “release” as used herein.

[0022] If at least four dosage forms are used, the fourth of the atleast four dosage form may be a sustained release dosage form or adelayed release dosage form. If the fourth dosage form is a sustainedrelease dosage form, even though C_(max) of the fourth dosage form ofthe at least four dosage forms is reached after the C_(max) of each ofthe other dosage forms is reached, antibiotic release from such fourthdosage form may be initiated prior to or after release from the secondor third dosage form.

[0023] In accordance with an aspect of the present invention, there isprovided an antibiotic composition that is a mixture of antibioticcompositions or dosage forms wherein said composition contains a firstcomposition or dosage form comprising a first antibiotic and apharmaceutically acceptable carrier; a second composition or dosage formcomprising the first antibiotic and a pharmaceutically acceptablecarrier; a third composition or dosage form comprising a secondantibiotic different from the first antibiotic and a pharmaceuticallyacceptable carrier; and a fourth composition or dosage form comprisingthe second antibiotic and a pharmaceutically acceptable carrier; whereinthe second and third compositions each have a release profile thatprovides a maximum serum concentration of the first antibiotic releasedfrom the second composition and a maximum serum concentration for thesecond antibiotic released from the third composition at a time afterthe first antibiotic released from the first composition reaches amaximum serum concentration, and wherein the fourth composition has arelease profile that provides for a maximum serum concentration of thesecond antibiotic released from the fourth composition at a time afterthe antibiotics released from the second and third compositions reach amaximum serum concentration. The first antibiotic is one ofcephalosporin or Metronidazole and the second antibiotic is the other ofcephalosporin or Metronidazole.

[0024] In one embodiment, the release profiles of the second and thirdcomposition are such that the maximum serum concentration of the firstantibiotic released from the second composition, and the maximum serumconcentration of the second antibiotic released from the thirdcomposition are reached at approximately the same time, or where thefirst antibiotic reaches a maximum serum concentration before or afterthe second antibiotic reaches a maximum serum concentration.

[0025] In effect, in accordance with a preferred embodiment of thepresent invention, there is provided a first pulse in which a firstantibiotic reaches a maximum serum concentration, a second pulse whereina further dosage of the first antibiotic, and an initial dosage of thesecond antibiotic reach a maximum serum concentration at a time afterthe first pulse of the first antibiotic reaches a maximum serumconcentration, and a third pulse wherein an additional dosage of thesecond antibiotic reaches a maximum serum concentration at a time afterthe maximum serum concentration is reached for each of the first andsecond antibiotic dosages provided in the second pulse.

[0026] In a preferred embodiment of the present invention, the firstdosage of the first antibiotic achieves a maximum serum concentrationwithin four hours after administration of the antibiotic composition;the second dosage of the first antibiotic and the first dosage of thesecond antibiotic each reach a maximum serum concentration within fourto eight hours after administration of the antibiotic composition; andthe second dosage of the second antibiotic reaches a maximum serumconcentration within twelve hours after administration of the antibioticcomposition.

[0027] Thus, in accordance with an aspect of the present invention,there is provided an antibiotic composition that includes four differentdosage forms, with the first dosage form providing an initial dosage ofa first antibiotic, the second dosage form providing a further dosage ofthe first antibiotic; the third dosage form providing an initial dosageof a second antibiotic; and the fourth dosage form providing anadditional dosage of the second antibiotic, wherein the antibioticsreleased from the second and third dosage forms reach a maximum serumconcentration at a time after the antibiotic released from the firstdosage form reaches a maximum serum concentration, and the antibioticreleased from the fourth dosage form reaching a maximum serumconcentration at a time after the times at which the antibioticsreleased from each of the first, second, and third dosage forms reach amaximum serum concentration.

[0028] In one embodiment of the invention, the first dosage formprovides for immediate release, the second and third dosage formsprovide for a delayed release (pH or non pH dependent, with the seconddosage form preferably being a pH dependent release), and the fourthdosage form provides for pH dependent or non pH dependent releasepreferably non pH dependent release.

[0029] In formulating the antibiotic composition of the presentinvention, which contains four different dosage forms, as hereinabovedescribed, the first dosage form generally contains from about 30percent to about 80 percent of the first antibiotic; the second dosageform contains from about 30 percent to about 80 percent of the firstantibiotic; the third dosage form contains from about 30 percent toabout 80 percent of the second antibiotic, and the fourth antibioticdosage form contains from about 30 percent to about 80 percent of thesecond antibiotic. In formulating a composition comprised of such fourdosage forms or units, each unit or dosage form is present in an amountof at least 20 percent by weight, with each dosage form or unit beingpresent in the overall composition in an amount that generally does notexceed 60 percent by weight.

[0030] Each of the first and second dosage forms include from 20% to 80%of the total dosage of the first antibiotic to be provided by thecomposition, and each of the first and second dosage forms may includethe same or different dosages of the first antibiotic.

[0031] Each of the third and fourth dosage forms include from 20% to 80%of the total dosage of the second antibiotic to be delivered by thecomposition, and each of the third and fourth units may have the same ordifferent dosages of the antibiotic.

[0032] In formulating an antibiotic product in accordance with theinvention, in one embodiment, the immediate release dosage form of theproduct generally provides from about 20% to about 50% of the totaldosage of antibiotic to be delivered by the product, with such immediaterelease dosage form generally providing at least 25% of the total dosageof the antibiotic to be delivered by the product. In many cases, theimmediate release dosage form provides from about 20% to about 30% ofthe total dosage of antibiotic to be delivered by the product; however,in some cases it may be desirable to have the immediate release dosageform provide for about 45% to about 50% of the total dosage ofantibiotic to be delivered by the product.

[0033] The remaining dosage forms deliver the remainder of theantibiotic. If more than one delayed release dosage form is used, in oneembodiment, each of the delayed release dosage forms may provide aboutequal amounts of antibiotic; however, they may also be formulated so asto provide different amounts.

[0034] In one embodiment, where the composition contains one immediaterelease component and two delayed release components, the immediaterelease component provides from 20% to 35% (preferably 20% to 30%), byweight, of the total antibiotic; where there is three delayed releasecomponents, the immediate release component provides from 15% to 30%, byweight, of the total antibiotic; and where there are four delayedrelease components, the immediate release component provides from 10% to25%, by weight, of the total antibiotic.

[0035] With respect to the delayed release components, where there aretwo delayed release components, the first delayed release component (theone released earlier in time) provides from 30% to 60%, by weight, ofthe total antibiotic provided by the two delayed release components withthe second delayed release component providing the remainder of theantibiotic.

[0036] Where there are three delayed release components, the earliestreleased component provides 20% to 35% by weight of the total antibioticprovided by the three delayed release components, the next in timedelayed release component provides from 20% to 40%, by weight, of theantibiotic provided by the three delayed release components and the lastin time providing the remainder of the antibiotic provided by the threedelayed release components.

[0037] When there are four delayed release components, the earliestdelayed release component provides from 15% to 30%, by weight, the nextin time delayed release component provides from 15% to 30%, the next intime delayed release component provides from 20% to 35%, by weight, andthe last in time delayed release component provides from 20% to 35%, byweight, in each case of the total antibiotic provided by the fourdelayed release components.

[0038] The overall composition includes each of the antibiotics in atherapeutically effective amount. The specific amount(s) is dependant onthe antibiotic used, the disease or infection to be treated, and thenumber of times of day that the composition is to be administered.

[0039] The antibiotic composition of the present invention may beadministered for example, by any one of the following routes ofadministration: sublingual, transmucosal, transdermal, parenteral, oral,preferably by oral administration.

[0040] The antibiotic product of the present invention, as hereinabovedescribed, may be formulated for administration by a variety of routesof administration. For example, the antibiotic product may be formulatedin a way that is suitable for topical administration; administration inthe eye or the ear; rectal or vaginal administration; as nose drops; byinhalation; as an injectable; or for oral administration. In a preferredembodiment, the antibiotic product is formulated in a manner such thatit is suitable for oral administration.

[0041] For example, in formulating the antibiotic product for topicaladministration, such as by application to the skin, the at least twodifferent dosage forms, each of which contains an antibiotic, may beformulated for topical administration by including such dosage forms inan oil-in-water emulsion, or a water-in-oil emulsion. In such aformulation, the immediate release dosage form is in the continuousphase, and the delayed release dosage form is in a discontinuous phase.The formulation may also be produced in a manner for delivery of threedosage forms as hereinabove described. For example, there may beprovided an oil-in-water-in-oil emulsion, with oil being a continuousphase that contains the immediate release component, water dispersed inthe oil containing a first delayed release dosage form, and oildispersed in the water containing a third delayed release dosage form.

[0042] It is also within the scope of the invention to provide anantibiotic product in the form of a patch, which includes antibioticdosage forms having different release profiles, as hereinabovedescribed.

[0043] In addition, the antibiotic product may be formulated for use inthe eye or ear or nose, for example, as a liquid emulsion. For example,the dosage form may be coated with a hydrophobic polymer whereby adosage form is in the oil phase of the emulsion, and a dosage form maybe coated with hydrophilic polymer, whereby a dosage form is in thewater phase of the emulsion.

[0044] Furthermore, the antibiotic product with at least three differentdosage forms with different release profiles may be formulated forrectal or vaginal administration, as known in the art. This may take theform of a cream or emulsion, or other dissolvable dosage form similar tothose used for topical administration.

[0045] As a further embodiment, the antibiotic product may be formulatedfor use in inhalation therapy by coating the particles and micronizingthe particles for inhalation.

[0046] In a preferred embodiment, the antibiotic product is formulatedin a manner suitable for oral administration. Thus, for example, fororal administration, each of the dosage forms may be used as a pellet ora particle, with a pellet or particle then being formed into a unitarypharmaceutical product, for example, in a capsule, or embedded in atablet, or suspended in a liquid for oral administration.

[0047] Alternatively, in formulating an oral delivery system, each ofthe dosage forms of the product may be formulated as a tablet, with eachof the tablets being put into a capsule to produce a unitary antibioticproduct. Thus, for example, antibiotic products may include a firstdosage form in the form of a tablet that is an immediate release tablet,and may also include two or more additional tablets, each of whichprovides for a delayed release of the antibiotic, as hereinabovedescribed, whereby the C_(max) of the antibiotic released from each ofthe tablets is reached at different times, with the C_(max) of the totalantibiotic released from the antibiotic product being achieved in lessthan twelve hours.

[0048] The formulation of an antibiotic product including at least threedosage forms with different release profiles for different routes ofadministration is deemed to be within the skill of the art from theteachings herein. As known in the art, with respect to delayed release,the time of release can be controlled by the concentration ofantibiotics in the coating and/or the thickness of the coating.

[0049] As hereabove indicated, the first and second antibiotics employedin the antibiotic composition may be a wide variety of products. In oneembodiment, the combination of first and second antibiotics that areused in the composition may be, for example, a penicillin and anaminoglycoside, such as gentamycin, tobramicin, amikacin or vancomycin.Another antibiotic composition that may be employed is a combination ofa sulfonamide, such as sulfamethoxasol, which would be combined withtrimethoporim. In a preferred embodiment, the first and second,antibiotics are different antibiotics and each is from a different classof antibiotic.

[0050] The Immediate Release Component

[0051] The immediate release portion of this system can be a mixture ofingredients that breaks down quickly after administration to release theantibiotic. This can take the form of either a discrete pellet orgranule that is mixed in with, or compressed with, the other threecomponents.

[0052] The materials to be added to the antibiotics for the immediaterelease component can be, but are not limited to, microcrystallinecellulose, corn starch, pregelatinized starch, potato starch, ricestarch, sodium carboxymethyl starch, hydroxypropylcellulose,ydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose,chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linkedchitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol,sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose,polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol,Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs(PEG2000-10000) and high molecular weight PEGs (Polyox) with molecularweights above 20,000 daltons.

[0053] It may be useful to have these materials present in the range of1.0 to 60% (W/W).

[0054] In addition, it may be useful to have other ingredients in thissystem to aid in the dissolution of the drug, or the breakdown of thecomponent after ingestion or administration. These ingredients can besurfactants, such as sodium lauryl sulfate, sodium monoglycerate,sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitanmonooleate, glyceryl monostearate, glyceryl monooleate, glycerylmonobutyrate, one of the non-ionic surfactants such as the Pluronic lineof surfactants, or any other material with surface active properties, orany combination of the above.

[0055] These materials may be present in the rate of 0.05-15% (W/W).

[0056] The Delayed Release Component

[0057] The components in this composition are the same immediate releaseunit, but with additional polymers integrated into the composition, oras coatings over the pellet or granule.

[0058] Materials that can be used to obtain a delay in release suitablefor this component of the invention can be, but are not limited to,polyethylene glycol (PEG) with molecular weight above 4,000 daltons(Carbowax, Polyox), waxes such as white wax or bees wax, paraffin,acrylic acid derivatives (Eudragit), propylene glycol, andethylcellulose.

[0059] Typically these materials can be present in the range of 0.5-25%(W/W) of this component.

[0060] The Enteric Release Component

[0061] The components in this composition are the same as the immediaterelease component, but with additional polymers integrated into thecomposition, or as coatings over the pellet or granule.

[0062] The kind of materials useful for this purpose can be, but are notlimited to, cellulose acetate pthalate, Eudragit L, and other pthalatesalts of cellulose derivatives.

[0063] These materials can be present in concentrations from 4-20%(W/W).

[0064] The invention will be further described with respect to thefollowing examples; however the scope of the invention is not limitedthereby. All percentages stated in this specification are by weight,unless otherwise specified.

EXAMPLES

[0065] Ingredient Conc. (% W/W) Immediate Release Component Example 1:Amoxicillin 65% (W/W) Microcrystalline cellulose 20 Povidone 10Croscarmellose sodium  5 Example 2: Amoxicillin 55% (W/W)Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10Example 3: Amoxicillin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 4:Amoxicillin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose  5 Example 5: Amoxicillin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone  5 Example 6:Clarithromycin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 7:Clarithromycin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose  5 Croscarmellose sodium  5 Example 8:Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose  5 Example 9: Clarithromycin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone  5 Example 10:Ciprofoxacin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 11:Ciprofoxacin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose  5 Croscarmellose sodium  5 Example 12:Ciprofoxacin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol2000 10 Hydroxypropylcellulose  5 Example 13: Cirpofoxacin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone  5 Example 14:Ceftibuten 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose  5 Example 15: Ceftibuten 75% (W/W)Polyethylene Glycol 4000 20 Polyvinylpyrrolidone  5 Delayed ReleaseComponent (non-pH dependant) Example 16: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium  5 Example17: Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Polyox 10Glyceryl monooleate 10 Example 18: Amoxicillin 65% (W/W) Polyox 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 19:Amoxicillin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Eudragit RL 30D  5 Example 20: Amoxicillin 75% (W/W)Polyethylene glycol 8000 20 Ethylcellulose  5 Example 21: Clarithromycin70% (W/W) Polyox 20 Hydroxypropylcellulose  5 Croscarmellose sodium  5Example 22: Clarithromycin 75% (W/W) Polyox 15 Hydroxypropylcellulose  5Ethylcellulose  5 Example 23: Clarithromycin 75% (W/W) Polyethyleneglycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D  5 Example24: Clarithromycin 80% (W/W) Polyethylene glycol 8000 10Polyvinylpyrrolidone  5 Eudgragit R 30D  5 Example 25: Ciprofoxacin 65%(W/W) Polyethylene glycol 4000 20 Hydroxypropylcellulose 10 Eudragit RL30D  5 Example 26: Ciprofoxacin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose  5 Ethylcellulose  5 Example 27: Ciprofoxacin 80%(W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000  5 EudgragitRL 30D  5 Example 28: Ciprofoxacin 75% (W/W) Polyethylene glycol 8000 20Ethylcellulose  5 Example 29: Ceftibuten 75% (W/W) Polyethylene glycol4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D  5 Example 30:Ceftibuten 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose  5Example 31: Gentamicin 20% (W/W) Sodium lauryl sulfate  2 Sodiummonoglycerides 10 Sodium diglycerides 20 Diethyleneglycolmethylether  5Microcrystalline cellulose 43 Example 32: Gentamicin 10% (W/W) Glyvcerylbehanate 30 Pluronic 10 Carbopol 94P 30 Microcrystalline cellulose 20Example 33: Gentamicin 25% (W/W) Carbopol 94P 35 Microcrystallinecellulose 20 Vitamin E TPGS 15 Sodium monoglycerate  5 Example 34:Amikacin 25% (W/W) Carbopol 94P 10 Sodium monoglycerate 15 Sodiumdiglycerate 15 Pluronic 10 Lactose 25 Example 35: Gentamicin 30% (W/W)Triacetin 15 Capryol 90  5 Poloxamer Synperonic PE/F66 10 Cab-O-Sil  5Microcrystalline cellulose 35 Enteric Release Component Example 36:Clarithromycin 70% (W/W) Hydroxypropylcellulose 15 pthalate 10Croscarmellose sodium Example 37: Clarithromycin 70% (W/W) Eudragit E30D15 Hydroxypropylcellulose 10 Ethylcellulose  5 Example 38:Clarithromycin 75% (W/W) Polyethylene glycol 2000 10 Eudragit E 30D 15Example 39: Clarithromycin 40% (W/W) Lactose 50 Eudgragit E 30D 10Example 40: Ciprofoxacin 65% (W/W) Microcrystalline Cellulose 20Eudragit E 30D 10 Example 41: Ciprofoxacin 75% (W/W) MicrocrystallineCellulose 15 Hydroxypropylcellulose 10 pthalate Example 42: Ciprofoxacin80% (W/W) Lactose 10 Eudragit E 30D 10 Example 43: Ciprofoxacin 70%(W/W) Polyethylene glycol 4000 20 Cellulose acetate pthalate 10 Example44: Ceftibuten 60% (W/W) Polyethylene glycol 2000 10 Lactose 20 EudragitE 30D 10 Example 45: Ceftibuten 70% (W/W) Microcrystalline cellulose 20Cellulose acetate pthalate 10 Example 46: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example 47:Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Cellulose AcetatePthalate 10 Hydroxypropylmethylcellulose 10 Example 48: Amoxicillin 65%(W/W) Polyox 20 Hydroxypropylcellulose 10 pthalate  5 Eudragit E30DExample 49: Amoxicillin 75% (W/W) Polyethylene glycol 2000 10 EudragitE30D 10 Eudragit RL 30D  5 Example 50: Amoxicillin 40% (W/W)Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10 Example 51:Ceftibuten 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose  5Example 52: Gentamicin 20% (W/W) Sodium lauryl sulfate  2 Sodiummonoglycerides 10 Sodium diglycerides 20 Diethyleneglycolmethylether  5Microcrystalline cellulose 30 Cellulose acetate pthalate 13 Example 53:Gentamicin 10% (W/W) Glyceryl behanate 30 Pluronic 10 Carbopol 94P 10Microcrystalline cellulose 20 Eudragit E30D 20 Example 54: Gentamicin25% (W/W) Carbopol 94P 15 Microcrystalline cellulose 20 Vitamin E TPGS15 Sodium Monoglycerate  5 Eudragit E30D 20 Example 55: Amikacin 25%(W/W) Carbopol 94P 10 Sodium monoglycerate 15 Sodium diglycerate 15Pluronic 10 Lactose 15 Cellulose acetate pthalate 10 Example 56:Gentamicin 30% (W/W) Triacetin 15 Capryol 90  5 Poloxamer SynperonicPE/F66 10 Cab-O-Sil  5 Microcrystalline cellulose 25 Eudragit E30D 10

[0066] Three Pulses

Example 57

[0067] 1. Antibiotic Matrix Pellet Formulation and Preparation Procedure(Immediate Release)

[0068] A. Pellet Formulation

[0069] The composition of the antibiotic matrix pellets provided inTable 1. TABLE 1 Composition of Antibiotic Pellets Component Percentage(%) Antibiotic 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 PurifiedWater Total 100

[0070] B. Preparation Procedure for antibiotic Matrix Pellets

[0071] 1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupehigh shear granulator.

[0072] 1.2.2 Add 20% Povidone K29/32 binder solution slowly into thepowder blend under continuous mixing.

[0073] 1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0074] 1.2.4 Spheronize the extrudate using a Model SPH20 CalevaSpheronizer.

[0075] 1.2.5 Dry the spheronized pellets at 50° C. overnight.

[0076] 1.2.6 Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0077] The above procedure is used to make pellets of a first antibioticand pellets of a second different antibiotic.

[0078] 1.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0079] A. Dispersion Formulation

[0080] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the antibiotic matrix pellets is provided below in Table 2.TABLE 2 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

[0081] B. Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0082] 1.3.1 Suspend triethyl citrate and talc in deionized water.

[0083] 1.3.2 The TEC/talc suspension is then homogenized using aPowerGen 700 high shear mixer.

[0084] 1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

[0085] 1.3.4 Allow the coating dispersion to stir for one hour prior toapplication onto the antibiotic matrix pellets.

[0086] 1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0087] A. Dispersion Formulation

[0088] The composition of the aqueous Eudragit® S 100 dispersion appliedto the antibiotic matrix pellets is provided below in Table 3. TABLE 3Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 Solid Content20.0 Polymer Content 12.0

[0089] B. Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0090] Part I:

[0091] (i) Dispense Eudragit® S 100 powder in deionized water withstirring.

[0092] (ii) Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0093] (iii) Allow the partially neutralized dispersion to stir for 60minutes.

[0094] (iv) Add triethyl citrate drop-wise into the dispersion withstirring. Stir for about 2 hours prior to the addition of Part B.

[0095] Part II:

[0096] (i) Disperse talc in the required amount of water

[0097] (ii) Homogenize the dispersion using a PowerGen 700D high shearmixer.

[0098] (iii) Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0099] 1.5 Coating Conditions for the Application of Aqueous CoatingDispersions

[0100] The following coating parameters are used to coat matrix pelletswith each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous filmcoating. Coating Equipment STREA 1 ™ Table Top Laboratory Fluid BedCoater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet AirTemperature 40 to 45° C. Outlet Air Temperature 30 to 33° C. AtomizationAir Pressure 1.8 Bar Pump Rate 2 gram per minute

[0101] (i) Coat matrix pellets with L30 D-55 dispersion such that youapply 12% coat weight gain to the pellets.

[0102] (ii) Coat matrix pellets with S100 dispersion such that you apply20% coat weight gain to the pellets.

[0103] 1.6 Encapsulation of the Antibiotic Pellets

[0104] Pellets are filled into size 00 hard gelatin capsules at a ratioof 30%: 30%: 40%: Immediate-release matrix pellets uncoated, L30 D-55coated pellets and S100 coated pellets respectively.

[0105] The capsule is filled with the three different pellets to achievea the desire dosage.

[0106] The immediate release matrix pellets include the firstantibiotic, the L30 D-55 coated pellets are made by coating matrixpellets that contain the second antibiotic and the S100 coated pelletsare made by coating matrix pellets that contain the first antibiotic.

[0107] Three Pulses

Example 58

[0108] Antibiotic Pellet Formulation and Preparation Procedure

[0109] 58.1 Pellet Formulations for subsequent coating

[0110] The composition of the Antibiotictrihydrate matrix pelletsprovided in Table 4. TABLE 4 Composition of AntibioticMatrix PelletsComponent Percentage (%) AntibioticTrihydrate powder 92 Avicel PH 1017.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100

[0111] 58.2 Preparation Procedure for AntibioticMatrix Pellets

[0112] 58.2.1 Blend Antibioticand Avicel® PH 101 using a low shearblender.

[0113] 58.2.2 Add the hydroxypropyl methylcellulose binder solutionslowly into the powder blend under continuous mixing.

[0114] 58.2.3 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator is 0.8 mm.

[0115] 58.2.4 Spheronize the extrudate using a QJ-230 Spheronizer usinga small cross section plate.

[0116] 58.2.5 Dry the spheronized pellets at 60° C. using a fluid beddryer until the exhaust temperature reaches 40° C.

[0117] 58.2.6 Pellets between 20 and 40 Mesh were collected for furtherprocessing.

[0118] 58.2.7 The above procedure is used to produce pellets thatcontain a first antibiotic and pellets that contain a second anddifferent antibiotic.

[0119] 58.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0120] 58.3.1 Dispersion Formulation

[0121] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the Antibioticmatrix pellets is provided below in Table 5.TABLE 5 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 41.6 Triethyl Citrate 2.5 Talc 5.0Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5

[0122] 58.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0123] 58.4.1 Suspend triethyl citrate and talc in deionized water.

[0124] 58.4.2 The TEC/talc suspension is mixed using laboratory mixer.

[0125] 58.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L30 D-55 latex dispersion while stirring.

[0126] 58.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the Antibioticmatrix pellets.

[0127] 58.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0128] 58.5.1 Dispersion Formulation

[0129] The composition of the aqueous Eudragit® S 100 dispersion appliedto the Antibioticmatrix pellets is provided below in Table 6. TABLE 6Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1 Triethyl Citrate5.0 Water 64.9 Part B Talc 5.0 Water 10.0 Solid Content 25.0 PolymerContent 10.0

[0130]58.6 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0131] Part A:

[0132] 58.6.1 Dispense Eudragit® S 100 powder in deionized water withstirring.

[0133] 58.6.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0134] 58.6.3 Allow the partially neutralized dispersion to stir for 60minutes.

[0135] 58.6.4 Add triethyl citrate drop-wise into the dispersion withstirring and let stir overnight prior to the addition of Part B.

[0136] Part B:

[0137] 58.6.5 Disperse talc in the required amount of water

[0138] 58.6.6 Stir the dispersion using an overhead laboratory mixer.

[0139] 58.6.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0140] 58.7 Coating Conditions for the Application of Aqueous CoatingDispersions

[0141] The following coating parameters are used for both the Eudragit®L 30 D-55 and Eudragit® S 100 aqueous film coating processes. CoatingEquipment STREA 1 ™ TAble Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45°C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure 1.8 BarPump Rate 2-6 gram per minute

[0142] 58.7.1 Coat matrix pellets with L30 D-55 dispersion such that youapply 20% coat weight gain to the pellets.

[0143] 58.7.2 Coat matrix pellets with S100 dispersion such that youapply 37% coat weight gain to the pellets.

[0144] 58.8 Preparation of AntibioticGranulation (Immediate ReleaseComponent) for tabletting TABLE 7 Composition of AntibioticGranulationComponent Percentage (%) AntibioticTrihydrate powder 92 Avicel PH 1017.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100

[0145] 58.8.1 Blend Antibioticand Avicel® PH 101 using a low shearblender.

[0146] 58.8.2 Add the hydroxypropyl methylcellulose binder solutionslowly into the powder blend under continuous mixing.

[0147] 58.8.3 Dry the granulation at 60° C. using a fluid bed dryeruntil the exhaust temperature reaches 40° C.

[0148] 58.8.4 Granules between 20 and 40 Mesh are collected for furtherprocessing.

[0149] 58.9 Tabletting of the AntibioticPellets TABLE 8 Composition ofAntibioticTablets Component Percentage (%) First antibioticgranules 32.5Avicel PH 200 5.0 Second antibioticL30D-55 coated pellets 30 FirstantibioticS100 coated pellets 30 Colloidal silicon dioxide 1.5 Magnesiumstearate 1.0 Total 100

[0150] 58.9.1 Blend the Antibioticgranules, Avicel PH-200,Antibioticpellets and colloidal silicon dioxide for 15 minutes in atumble blender.

[0151] 58.9.2 Add the magnesium stearate to the blender, and blend for 5minutes.

[0152] 58.9.3 Compress the blend on a rotary tablet press.

[0153] 58.9.4 The fill weight should be adjusted to achieve the desireddosage.

[0154] Four pulses

Example 59

[0155] 1 Antibiotic Matrix Pellet Formulation and Preparation Procedure

[0156] 59.1 Pellet Formulation

[0157] The composition of the antibiotic matrix pellets provided inTable 9. TABLE 9 Composition of Antibiotic Pellets Component Percentage(%) Antibiotic 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 PurifiedWater Total 100

[0158] 59.2 Preparation Procedure for Antibiotic Matrix Pellets

[0159] 59.2.1 Blend antibiotic and Avicel® PH 101 using a Robot Coupehigh shear granulator.

[0160] 59.2.2 Add 20% Povidone K29/32 binder solution slowly into thepowder blend under continuous mixing.

[0161] 59.2.3 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator was 1.0 mm.

[0162] 59.2.4 Spheronize the extrudate using a Model SPH20 CalevaSpheronizer.

[0163] 59.2.5 Dry the spheronized pellets at 50° C. overnight.

[0164] 59.2.6 Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0165] 59.2.7 The above procedure is used to prepare pellets thatcontain a first antibiotic and pellets that contain a second antibiotic.

[0166] 59.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0167] 59.3.1 Dispersion Formulation

[0168] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the antibiotic matrix pellets is provided below in Table 10.TABLE 10 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

[0169]59.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0170] 59.4.1 Suspend triethyl citrate and talc in deionized water.

[0171] 59.4.2 The TEC/talc suspension is then homogenized using aPowerGen 700 high shear mixer.

[0172] 59.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

[0173] 59.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the antibiotic matrix pellets.

[0174] 59.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0175] 59.5.1 Dispersion Formulation

[0176] The composition of the aqueous Eudragit® S 100 dispersion appliedto the antibiotic matrix pellets is provided below in Table 11. TABLE 11Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 Solid Content20.0 Polymer Content 12.0

[0177]59.6 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0178] Part A:

[0179] 59.6.1 Dispense Eudragit® S 100 powder in deionized water withstirring.

[0180] 59.6.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0181] 59.6.3 Allow the partially neutralized dispersion to stir for 60minutes.

[0182] 59.6.4 Add triethyl citrate drop-wise into the dispersion withstirring. Stir for about 2 hours prior to the addition of Part B.

[0183] Part B:

[0184] 59.6.5 Disperse talc in the required amount of water

[0185] 59.6.6 Homogenize the dispersion using a PowerGen 700D high shearmixer.

[0186] 59.6.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0187] 59.7 Coating Conditions for the Application of Aqueous CoatingDispersions

[0188] The following coating parameters are used for coating with eachof the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.8 Bar Pump Rate 2 gram per minute

[0189] 59.7.1 Coat matrix pellets with L30 D-55 dispersion such that youapply 12% coat weight gain to the pellets.

[0190] 59.7.2 Coat matrix pellets with L30 D-55 dispersion such that youapply 30% coat weight gain to the pellets.

[0191] 59.7.3 Coat matrix pellets with S100 dispersion such that youapply 20% coat weight gain to the pellets.

[0192] 59.8 Encapsulation of the Antibiotic Pellets

[0193] Pellets are filled into size 00 hard gelatin capsules at a ratioof 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weightgain and S100 coated pellets respectively. The capsule is filled withthe four different pellets to achieve the desired dosage.

[0194] The immediate release pellets contain the first antibiotic; theL30 D-55 12% weight gain coated pellets containe the second antibiotic;the L30 D-55 30% weight gain coated pellets contain the first antibioticand the S100 coated pellets contain the second antibiotic.

Example 60

[0195] Metronidazole Pellet Formulation and Preparation Procedure

[0196] Pellet Formulations

[0197] The composition of the Metronidazole pellets provided in Table12. TABLE 12 Composition of Metronidazole Pellets Component Percentage(%) Metronidazole 93  Avicel PH 101 3 Methocel E5P LV 4 Purified Water *Total 100 

[0198] Procedure for Metronidazole Pellets

[0199] Blend metronidazole, Avicel® PH 101, and Methocel using a RobotCoupe high shear granulator.

[0200] Add the purified water slowly into the powder blend undercontinuous mixing.

[0201] Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0202] Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0203] Dry the spheronized pellets at 50° C. until moisture level is<3%.

[0204] Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0205] Metronidazole Delayed Enteric-Release Pellets Formulation andPreparation Procedure

[0206] Preparation of an Opadry Clear Coating Solution

[0207] Dispersion Formulation

[0208] The composition of the aqueous Opadry solution applied to themetronidazole pellets is provided below in Table 13. TABLE 13 OpadryClear Aqueous Coating Solution Component Percentage (%) Opadry ClearYS-1-7006 7.0 Purified Water* 93.0 Solid Content % 7.0 Polymer Content %7.0

[0209] Preparation Procedure for Opadry Clear Aqueous Solution

[0210] Charge the purified water into a container

[0211] Slowly add the Opadry Clear YS-1-7006 to the water withcontinuous mixing.

[0212] Preparation of an AQOAT AS-HF/Eudragit® FS30D Aqueous CoatingDispersion

[0213] Dispersion Formulation

[0214] The composition of the aqueous AQOAT AS-HF/ Eudragit FS30Dcoating dispersion applied to the Opadry coated metronidazole pellets isprovided below in Table 14. TABLE 14 AQOAT AS-HF/ Eudragit FS 30DCoating Dispersion Component Percentage (%) AQOAT AS-HF 5.25 EudragitFS30D 5.83 Triethyl Citrate 1.96 Sodium Lauryl Sulfate 0.21 Talc 2.10Purified Water* 84.65 Solid Content 11.27 Polymer Content 7.0

[0215] Preparation Procedure for AQOAT AS-HF/ Eudragit FS30D AqueousDispersion

[0216] Disperse triethyl citrate in purified water with stirring.

[0217] Slowly add sodium lauryl sulfate into the triethyl citratedispersion with stirring.

[0218] Slowly add the AQOAT AS-HF powder to the dispersion above andstir for a minimum of 30 minutes.

[0219] Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HFdispersion and continue to stir for a minimum of 1 hour.

[0220] Slowly add the talc to the coating dispersion and continue tostir for at least 2 hours.

[0221] Screen the dispersion through a No. 60 mesh sieve.

[0222] Continue to stir the screened coating dispersion throughout thecoating process.

[0223] Coating Conditions for the Application of Opadry andAQOAT/Eudragit FS30D Aqueous Coating Dispersions

[0224] The following coating parameters were used for coating with theOpadry solution film coating. Coating Equipment STREA 1 ™ Table TopLaboratory Fluid Bed Coater Spray nozzle diameter 1.0 mm Material Charge350 gram Inlet Air Temperature 60° C. Outlet Air Temperature 40° C.Atomization Air Pressure 1.6 Bar

[0225] Coat metronidazole pellets with Opadry coating solution such thatyou apply 3% coat weight gain to the pellets.

[0226] The following coating parameters were used for coating with theAQOATAS-HF/Eudragit FS30D film coating dispersion. Coating EquipmentSTREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter1.0 mm Material Charge 300 gram Inlet Air Temperature 50° C. Outlet AirTemperature 30° C. Atomization Air Pressure 1.6 Bar

[0227] Coat Opadry coated metronidazole pellets with theAQOATAS-HF/Eudragit FS30D coating dispersion such that you apply 32%coat weight gain to the pellets. Dry the coated pellets in the fluid bedfor 20 minutes at 50° C.

[0228] Cefuroxime axetil Pellet Formulation and Preparation Procedure

[0229] Pellet Formulation

[0230] The composition of the Cefuroxime axetil pellets provided inTable 15. TABLE 15 Composition of Cefuroxime axetil Pellets ComponentPercentage (%) Cefuroxime axetil 93 Avicel PH 101 3 Methocel E5P LV 4Purified Water * Total 100

[0231] Preparation Procedure for Cefuroxime axetil Pellets

[0232] Blend Cefuroxime axetil, Avicel® PH 101, and Methocel using aRobot Coupe high shear granulator.

[0233] Add the purified water slowly into the powder blend undercontinuous mixing.

[0234] Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0235] Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0236] Dry the spheronized pellets at 50° C. until moisture level is<3%.

[0237] Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0238] Cefuroxime axetil Enteric-Release Pellet Formulation andPreparation Procedure

[0239] Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D AqueousCoating Dispersion

[0240] Dispersion Formulation

[0241] The composition of the aqueous Eudragit L30D-55/Eudragit NE 30Daqueous coating dispersion applied to the Cefuroxime axetil pellets isprovided below in Table 16. TABLE 16 Eudragit ® L 30 D-55/Eudragit NE30D Aqueous Coating Dispersion Component Percentage (%) Eudragit ® L30D-55 44.4 Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9Purified Water* 38.6 Solid Content 20.6 Polymer Content 16.4

[0242] Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30DAqueous Dispersion

[0243] Heat purified water to 75-80° C. and then add triethyl citrate(TEC) and Imwitor 900. Homogenize dispersion until temperature is lessthan 55° C.

[0244] The TEC/Imwitor 900 dispersion is then stirred until thetemperature is less than 35° C.

[0245] Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latexdispersion and stir for at least 30 minutes.

[0246] Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900dispersion and stir for at least 10 minutes.

[0247] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0248] Continue to stir the dispersion until the coating process iscomplete.

[0249] Coating Conditions for the Application of EudragitL30D-55/Eudragit NE 30DAqueous Coating Dispersion

[0250] The following coating parameters were used for coating of theEudragit® L 30 D-55/Eudragit NE30D film coating dispersion. CoatingEquipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 45° C.Outlet Air Temperature 32 to 35° C. Atomization Air Pressure 1.6 BarPump Rate 3-4 gram per minute

[0251] Coat Cefuroxime axetil pellets with Eudragit L30 D-55/Eudragit NE30D film coating dispersion such that you apply 20% coat weight gain tothe pellets.

[0252] Cefuroxime axetil Colonic-Release Pellets Formulation andPreparation Procedure

[0253] Preparation of an Eudragit® FS30D Aqueous Coating Dispersion

[0254] Dispersion Formulation

[0255] The composition of the aqueous Eudragit® FS 30D dispersionapplied to the Cefuroxime axetil pellets is provided below in Table 17.TABLE 17 Eudragit ® FS 30D Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® FS 30D 54.8 Triethyl Citrate 0.9 Talc 3.3Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4

[0256] Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

[0257] Disperse triethyl citrate (TEC) in the purified water.

[0258] Add the talc in the triethyl citrate dispersion.

[0259] Homogenize the dispersion using a homogenizer.

[0260] Add slowly the Eudragit® FS 30D dispersion to the talc/TECdispersion with stirring.

[0261] Continue to stir the coating dispersion until the coating processis complete.

[0262] Coating Conditions for the Application of Eudragit FS30D AqueousCoating Dispersion

[0263] The following coating parameters were used for coating with eachof the Eudragit® FS 30 D aqueous film coating. Coating Equipment STREA1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter 1.2 mmMaterial Charge 300 gram Inlet Air Temperature 38° C. Outlet AirTemperature 22° C. Atomization Air Pressure 1.6 Bar Pump Rate 6 gram perminute

[0264] Coat pellets with Eudragit FS 30D coating dispersion dispersionsuch that you apply 30% coat weight gain to the pellets.

[0265] Metronidazole and Cefuroxime axetil Tablets

[0266] Preparation of Metronidazole Granulation for tableting TABLE 18Composition of Metronidazole Granulation (Immediate Release) ComponentPercentage (%) Metronidazole 42.5 Lactose monohydrate, spray dried 36.5Avicel PH 101 20.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100

[0267] Blend Metronidazole, lactose, and Avicel® PH 101 using a highshear mixer.

[0268] Add the hydroxypropyl methylcellulose binder solution slowly intothe powder blend under continuous mixing.

[0269] Dry the granulation at 60° C. using a fluid bed dryer until theexhaust temperature reaches 40° C.

[0270] Granules between 20 and 40 Mesh are collected for furtherprocessing.

[0271] Tableting of the Metronidazole and Cefuroxime axetil TABLE 19Composition of Metronidazole and Cefuroxime axetil Tablets ComponentPercentage (%) Metronidazole granules 45.0 Avicel PH 200 7.6 EudragitL30D-55/NE 30D coated Cefuroxime axetil 8.2 Pellets AQOAT/Eudragit FS30D coated Metronidazole 27.8 Pellets Eudragit FS 30D coated Cefuroximeaxetil Pellets 8.9 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0Total 100

[0272] Blend the Metronidazole granules, Avicel PH-200, Metronidazolecoated pellets, Cefuroxime axetil coated pellets and colloidal silicondioxide for 15 minutes in a tumble blender.

[0273] Add the magnesium stearate to the blender, and blend for 5minutes.

[0274] Compress the blend on a rotary tablet press.

[0275] The fill weight should be adjusted to achieve a 500 mg total dosetablet.

[0276] The present invention is particularly advantageous in that thereis provided an antibiotic product which provides an improvement overtwice a day administration of the antibiotic and an improvement over aonce a day administration of the antibiotic.

[0277] Numerous modification and variations of the present invention arepossible in light of the above teachings and therefore, within the scopeof the appended claims the invention may be practiced otherwise than asparticularly described.

Example 61

[0278] Metronidazole Pellet Formulation and Preparation Procedure

[0279] Pellet Formulation

[0280] The composition of the metronidazole pellets provided in Table20. TABLE 20 Composition of Metronidazole Pellets Component Percentage(%) Metronidazole 93 Avicel PH 101 3 Methocel E5P LV 4 Purified Water *Total 100

[0281] Preparation Procedure for Metronidazole Pellets

[0282] Blend metronidazole, Avicel® PH 101, and Methocel using a RobotCoupe high shear granulator.

[0283] Add the purified water slowly into the powder blend undercontinuous mixing.

[0284] Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0285] Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0286] Dry the spheronized pellets at 50° C. until moisture level is<3%.

[0287] Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0288] Metronidazole Enteric-Release Pellet Formulation and PreparationProcedure

[0289] Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D AqueousCoating Dispersion

[0290] Dispersion Formulation

[0291] The composition of the aqueous Eudragit L30D-55/Eudragit NE 30Daqueous coating dispersion applied to the Metronidazole pellets isprovided below in Table 21. TABLE 21 Eudragit ® L 30 D-55/Eudragit NE30D Aqueous Coating Dispersion Component Percentage (%) Eudragit ® L30D-55 44.4 Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9Purified Water* 38.6 Solid Content 20.6 Polymer Content 16.4

[0292] Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30DAqueous Dispersion

[0293] Heat purified water to 75-80° C. and then add triethyl citrate(TEC) and Imwitor 900. Homogenize dispersion until temperature is lessthan 55° C.

[0294] The TEC/Imwitor 900 dispersion is then stirred until thetemperature is less than 35° C.

[0295] Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latexdispersion and stir for at least 30 minutes.

[0296] Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900dispersion and stir for at least 10 minutes.

[0297] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0298] Continue to stir the dispersion until the coating process iscomplete.

[0299] Coating Conditions for the Application of EudragitL30D-55/Eudragit NE 30DAqueous Coating Dispersion

[0300] The following coating parameters were used for coating of theEudragit® L 30 D-55/Eudragit NE30D film coating dispersion. CoatingEquipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 45° C.Outlet Air Temperature 32 to 35° C. Atomization Air Pressure 1.6 BarPump Rate 3-4 gram per minute

[0301] Coat metronidazole pellets with Eudragit L30 D-55/Eudragit NE 30Dfilm coating dispersion such that you apply 20% coat weight gain to thepellets.

[0302] Metronidazole Delayed Enteric-Release Pellet Formulation andPreparation Procedure

[0303] Preparation of an Opadry Clear Coating Solution

[0304] Dispersion Formulation

[0305] The composition of the aqueous Opadry solution applied to themetronidazole pellets is provided below in Table 22. TABLE 22 OpadryClear Aqueous Coating Solution Component Percentage (%) Opadry ClearYS-1-7006 7.0 Purified Water* 93.0 Solid Content % 7.0 Polymer Content %7.0

[0306] Preparation Procedure for Opadry Clear Aqueous Solution

[0307] Charge the purified water into a container

[0308] Slowly add the Opadry Clear YS-1-7006 to the water withcontinuous mixing.

[0309] Preparation of an AQOAT AS-HF/Eudragit® FS30D Aqueous CoatingDispersion

[0310] Dispersion Formulation

[0311] The composition of the aqueous AQOAT AS-HF/Eudragit FS30D coatingdispersion applied to the Opadry coated metronidazole pellets isprovided below in Table 23. TABLE 23 AQOAT AS-HF/ Eudragit FS 30DCoating Dispersion Component Percentage (%) AQOAT AS-HF 5.25 EudragitFS30D 5.83 Triethyl Citrate 1.96 Sodium Lauryl Sulfate 0.21 Talc 2.10Purified Water* 84.65 Solid Content 11.27 Polymer Content 7.0

[0312] Preparation Procedure for AQOAT AS-HF/Eudragit FS30D AqueousDispersion

[0313] Disperse triethyl citrate in purified water with stirring.

[0314] Slowly add sodium lauryl sulfate into the triethyl citratedispersion with stirring.

[0315] Slowly add the AQOAT AS-HF powder to the dispersion above andstir for a minimum of 30 minutes.

[0316] Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HFdispersion and continue to stir for a minimum of 1 hour.

[0317] Slowly add the talc to the coating dispersion and continue tostir for at least 2 hours.

[0318] Screen the dispersion through a No. 60 mesh sieve.

[0319] Continue to stir the screened coating dispersion throughout thecoating process.

[0320] Coating Conditions for the Application of Opadry andAQOAT/Eudragit FS30D Aqueous Coating Dispersions

[0321] The following coating parameters were used for coating with theOpadry solution film coating. Coating Equipment STREA 1 ™ Table TopLaboratory Fluid Bed Coater Spray nozzle diameter 1.0 mm Material Charge350 gram Inlet Air Temperature 60° C. Outlet Air Temperature 40° C.Atomization Air Pressure 1.6 Bar

[0322] Coat metronidazole pellets with Opadry coating solution such thatyou apply 3% coat weight gain to the pellets.

[0323] The following coating parameters were used for coating with theAQOATAS-HF/Eudragit FS30D film coating dispersion. Coating EquipmentSTREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter1.0 mm Material Charge 300 gram Inlet Air Temperature 50° C. Outlet AirTemperature 30° C. Atomization Air Pressure 1.6 Bar

[0324] Coat Opadry coated metronidazole pellets with theAQOATAS-HF/Eudragit FS30D coating dispersion such that you apply 32%coat weight gain to the pellets. Dry the coated pellets in the fluid bedfor 20 minutes at 50° C.

[0325] Metronidazole Colonic-Release Pellet Formulation and PreparationProcedure

[0326] Preparation of an Eudragit® FS 30D Aqueous Coating Dispersion

[0327] Dispersion Formulation

[0328] The composition of the aqueous Eudragit® FS 30D dispersionapplied to the Metronidazole pellets is provided below in Table 24.TABLE 24 Eudragit ® FS 30D Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® FS 30D 54.8 Triethyl Citrate 0.9 Talc 3.3Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4

[0329] Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

[0330] Disperse triethyl citrate (TEC) in the purified water.

[0331] Add the talc in the triethyl citrate dispersion.

[0332] Homogenize the dispersion using a homogenizer.

[0333] Add slowly the Eudragit® FS 30D dispersion to the talc/TECdispersion with stirring.

[0334] Continue to stir the coating dispersion until the coating processis complete.

[0335] Coating Conditions for the Application of Eudragit FS30D AqueousCoating Dispersion

[0336] The following coating parameters were used for coating with eachof the Eudragit® FS 30 D aqueous film coating. Coating Equipment STREA1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter 1.2 mmMaterial Charge 300 gram Inlet Air Temperature 38° C. Outlet AirTemperature 22° C. Atomization Air Pressure 1.6 Bar Pump Rate 6 gram perminute

[0337] Coat pellets with Eudragit FS 30D coating dispersion dispersionsuch that you apply 30% coat weight gain to the pellets.

[0338] Cefuroxime axetil Pellet Formulation and Preparation Procedure

[0339] Pellet Formulation

[0340] The composition of the Cefuroxime axetil pellets provided inTable 25. TABLE 25 Composition of Cefuroxime axetil Pellets ComponentPercentage (%) Cefuroxime axetil 93 Avicel PH 101 3 Methocel E5P LV 4Purified Water * Total 100

[0341] Preparation Procedure for Cefuroxime axetil Pellets

[0342] Blend Cefuroxime axetil, Avicel® PH 101, and Methocel using aRobot Coupe high shear granulator.

[0343] Add the purified water slowly into the powder blend undercontinuous mixing.

[0344] Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0345] Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0346] Dry the spheronized pellets at 50° C. until moisture level is<3%.

[0347] Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0348] Cefuroxime axetil Enteric-Release Pellet Formulation andPreparation Procedure

[0349] Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D AqueousCoating Dispersion

[0350] Dispersion Formulation

[0351] The composition of the aqueous Eudragit L30D-55/Eudragit NE 30Daqueous coating dispersion applied to the Cefuroxime axetil pellets isprovided below in Table 26. TABLE 26 Eudragit ® L 30 D-55/Eudragit NE30D Aqueous Coating Dispersion Component Percentage (%) Eudragit ® L30D-55 44.4 Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9Purified Water* 38.6 Solid Content 20.6 Polymer Content 16.4

[0352] Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30DAqueous Dispersion

[0353] Heat purified water to 75-80° C. and then add triethyl citrate(TEC) and Imwitor 900. Homogenize dispersion until temperature is lessthan 55° C.

[0354] The TEC/Imwitor 900 dispersion is then stirred until thetemperature is less than 35° C.

[0355] Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latexdispersion and stir for at least 30 minutes.

[0356] Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900dispersion and stir for at least 10 minutes.

[0357] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0358] Continue to stir the dispersion until the coating process iscomplete.

[0359] Coating Conditions for the Application of EudragitL30D-55/Eudragit NE 30DAqueous Coating Dispersion

[0360] The following coating parameters were used for coating of theEudragit® L 30 D-55/Eudragit NE30D film coating dispersion. CoatingEquipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 45° C.Outlet Air Temperature 32 to 35° C. Atomization Air Pressure 1.6 BarPump Rate 3-4 gram per minute

[0361] Coat Cefuroxime axetil pellets with Eudragit L30 D-55/Eudragit NE30D film coating dispersion such that you apply 20% coat weight gain tothe pellets.

[0362] Cefuroxime axetil Delayed Enteric-Release Pellet Formulation andPreparation Procedure

[0363] Preparation of an Opadry Clear Coating Solution

[0364] Dispersion Formulation

[0365] The composition of the aqueous Opadry solution applied to theCefuroxime axetil pellets is provided below in Table 27. TABLE 27 OpadryClear Aqueous Coating Solution Component Percentage (%) Opadry ClearYS-1-7006 7.0 Purified Water* 93.0 Solid Content % 7.0 Polymer Content %7.0

[0366] Preparation Procedure for Opadry Clear Aqueous Solution

[0367] Charge the purified water into a container

[0368] Slowly add the Opadry Clear YS-1-7006 to the water withcontinuous mixing.

[0369] Preparation of an Eudragit® FS 30D/Eudragit L 30D-55 AqueousCoating Dispersion

[0370] Dispersion Formulation

[0371] The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55coating dispersion applied to the Opadry coated Cefuroxime axetilpellets is provided below in Table 28. TABLE 28 Eudragit FS 30D/EudragitL 30D-55 Coating Dispersion Component Percentage (%) Eudragit L 30D-555.8 Eudagit FS 30D 17.5 Triethyl Citrate 1.3 Talc 1.4 Purified Water*74.0 Solid Content 9.7 Polymer Content 7.0

[0372] Preparation Procedure for Eudragit FS 30D/Eudragit L 30D-55Aqueous Dispersion

[0373] Disperse triethyl citrate in purified water with stirring.

[0374] Slowly add talc into the triethyl citrate dispersion withstirring.

[0375] Slowly add the Eudragit L 30D-55 to the dispersion above and stirfor a minimum of 10 minutes.

[0376] Slowly add the Eudragit FS 30D dispersion to the Eudragit L30D-55 dispersion and continue to stir for a minimum of 1 hour.

[0377] Screen the dispersion through a No. 60 mesh sieve.

[0378] Continue to stir the screened coating dispersion throughout thecoating process.

[0379] Coating Conditions for the Application of Opadry and Eudragit FS30D/ Eudragit L 30D-55 Aqueous Coating Dispersions

[0380] The following coating parameters were used for coating with theOpadry solution film coating. Coating Equipment STREA 1 ™ Table TopLaboratory Fluid Bed Coater Spray nozzle diameter 1.0 mm Material Charge350 gram Inlet Air Temperature 60° C. Outlet Air Temperature 40° C.Atomization Air Pressure 1.6 Bar

[0381] Coat Cefuroxime axetil pellets with Opadry coating solution suchthat you apply 3% coat weight gain to the pellets.

[0382] The following coating parameters were used for coating with theEudragit FS 30D/Eudragit L30D-55 film coating dispersion. CoatingEquipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 50° C.Outlet Air Temperature 30° C. Atomization Air Pressure 1.6 Bar

[0383] Coat Opadry coated Cefuroxime axetil pellets with the EudragitFS30D/Eudragit L 30D-55 coating dispersion such that you apply 32% coatweight gain to the pellets.

[0384] Cefuroxime axetil Colonic-Release Pellet Formulation andPreparation Procedure

[0385] Preparation of an Eudragit® FS 30D Aqueous Coating Dispersion

[0386] Dispersion Formulation

[0387] The composition of the aqueous Eudragit® FS 30D dispersionapplied to the Cefuroxime axetil pellets is provided below in Table 29.TABLE 29 Eudragit ® FS 30D Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® FS 30D 54.8 Triethyl Citrate 0.9 Talc 3.3Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4

[0388] Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

[0389] Disperse triethyl citrate (TEC) in the purified water.

[0390] Add the talc in the triethyl citrate dispersion.

[0391] Homogenize the dispersion using a homogenizer.

[0392] Add slowly the Eudragit® FS 30D dispersion to the talc/TECdispersion with stirring.

[0393] Continue to stir the coating dispersion until the coating processis complete.

[0394] Coating Conditions for the Application of Eudragit FS30D AqueousCoating Dispersion

[0395] The following coating parameters were used for coating with eachof the Eudragit® FS 30 D aqueous film coating. Coating Equipment STREA1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter 1.2 mmMaterial Charge 300 gram Inlet Air Temperature 38° C. Outlet AirTemperature 22° C. Atomization Air Pressure 1.6 Bar Pump Rate 6 gram perminute

[0396] Coat pellets with Eudragit FS 30D coating dispersion dispersionsuch that you apply 30% coat weight gain to the pellets.

[0397] Metronidazole and Cefuroxime axetil Tablets

[0398] Preparation of Metronidazole and Cefuroxime axetil Granulationfor tableting TABLE 30 Composition of Metronidazole and Cefuroximeaxetil Granulation (Immediate Release) Component Percentage (%)Metronidazole Trihydrate powder 13.3 Cefuroxime axetil 9.0 Lactosemonohydrate, spray dried 56.7 Avicel PH 101 20.0 Hydroxypropylmethylcellulose, NF* 1.0 Total 100

[0399] Blend Metronidazole, Cefuroxime axetil, lactose, and Avicel® PH101 using a high shear mixer.

[0400] Add the hydroxypropyl methylcellulose binder solution slowly intothe powder blend under continuous mixing.

[0401] Dry the granulation at 60° C. using a fluid bed dryer until theexhaust temperature reaches 40° C.

[0402] Granules between 20 and 40 Mesh are collected for furtherprocessing.

[0403] Tableting of the Metronidazole and Cefuroxime axetil TABLE 31Composition of Metronidazole and Cefuroxime axetil Tablets ComponentPercentage (%) Metronidazole/Cefuroxime axetil granules 49.0 Avicel PH200 3.5 Eudragit L30D-55/NE 30D coated Metronidazole 8.4 PelletsEudragit L30D-55/NE 30D coated Cefuroxime axetil 5.6 Pellets AQOAT/Eudragit FS 30D coated Metronidazole 9.5 Pellets Eudragit FS 30D / L30Dcoated Cefuroxime axetil 6.3 Pellets Eudragit FS 30D coatedMetronidazole Pellets 9.1 Eudragit FS 30D coated Cefuroxime axetilPellets 6.1 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total100

[0404] Blend the Metronidazole/Cefuroxime axetil granules, AvicelPH-200, Metronidazole coated pellets, Cefuroxime axetil coated pelletsand colloidal silicon dioxide for 15 minutes in a tumble blender.

[0405] Add the magnesium stearate to the blender, and blend for 5minutes.

[0406] Compress the blend on a rotary tablet press.

[0407] The fill weight should be adjusted to achieve a 625 mg total dosetablet.

[0408] In one embodiment, cephalosporin will be dosed in an alternatepulse to Metronidazole. This will alternate the exposure to the bacteriain such a way as to make both antibiotics more effective than if theywere co-administered, and thereby competing with each other for sites onthe bacterial cell wall receptors, or sites within the bacterial cells.

[0409] In addition, even when cephalosporin and Metronidazole are notdelivered in alternate pulses, the dosage forms as hereinabove describedprovide for improved treatment of infection.

[0410] Numerous modifications and variations of the present inventionare possible in light of the above teachings; therefore, within thescope of the appended claims, the invention may be practiced otherwisethan as particularly described.

What is claimed is:
 1. An antibiotic product comprising: at least threedosage forms, each dosage form comprising an antibiotic and apharmaceutically acceptable carrier, one of said dosage forms includingat least cephalosporin, a second of said dosage forms including at leastMetronidazole.
 2. The product of claim 1 wherein each of the dosageforms has a different release profile.
 3. The product of claim 1 whereinthe first dosage form is an immediate release dosage form.
 4. Theproduct of claim 3 wherein the second and third dosage forms are delayedrelease dosage forms.
 5. The product of claim 4 wherein antibioticreleased from the second dosage form reaches a C_(max) in serum afterantibiotic released from the first dosage form reaches C_(max) in serum.6. The product of claim 5 wherein antibiotic released from the thirddosage form reaches C_(max) in serum after antibiotic released from thesecond dosage form reaches C_(max) in serum.
 7. The product of claim 6wherein total antibiotic released from the product reaches C_(max) inserum within twelve hours of administration.
 8. The product of claim 7wherein the product is a once a day product.
 9. The product of claim 1wherein each of the three dosage forms includes at least the first andsecond antibiotic.
 10. The product of claim 1 wherein the first dosageform includes the first antibiotic, the second dosage form includes thefirst and second antibiotic and the fourth dosage form includes thesecond antibiotic.
 11. An antibiotic product comprising: a first,second, third and fourth dosage form, said first dosage form comprisinga first antibiotic and a pharmaceutically acceptable carrier; saidsecond dosage form comprising said first antibiotic and apharmaceutically acceptable carrier; said third dosage form comprising asecond antibiotic different from the first antibiotic and apharmaceutically acceptable carrier; said fourth dosage form comprisingsaid second antibiotic and a pharmaceutically acceptable carrier, saidsecond and third dosage forms having a release profile whereby themaximum serum concentration of the first antibiotic and the secondantibiotic released from the second and third dosage forms is reached ata time later than the maximum serum concentration of the firstantibiotic released from the first dosage form, and wherein the maximumserum concentration of the second antibiotic released from the fourthdosage form reaches a maximum serum concentration at a time after themaximum serum concentration for the antibiotic released from each of thefirst, second and third dosage forms is reached, wherein the firstantibiotic form is one of cephalosporin or Metronidazole and the secondantibiotic is the other of cephalosporin or Metronidazole.
 12. Thecomposition of claim I wherein the first antibiotic released from thesecond dosage form, and the second antibiotic released from the thirddosage form reach a maximum serum concentration at about the same time.13. A process for treating a bacterial infection in a host comprising:administering to the host the antibiotic product of claim
 1. 14. Aprocess for treating a bacterial infection in a host comprising:administering to the host the antibiotic product of claim
 2. 15. Aprocess for treating a bacterial infection in a host comprising:administering to the host the antibiotic product of claim
 3. 16. Aprocess for treating a bacterial infection in a host comprising:administering to the host the antibiotic product of claim
 4. 17. Aprocess for treating a bacterial infection in a host comprising:administering to the host the antibiotic product of claim
 5. 18. Aprocess for treating a bacterial infection in a host comprising:administering to the host the antibiotic product of claim
 6. 19. Aprocess for treating a bacterial infection in a host comprising:administering to the host the antibiotic product of claim
 7. 20. Aprocess for treating a bacterial infection in a host comprising:administering to the host the antibiotic product of claim 8.